Topical fungicidal composition for dermatomycosis of animals

ABSTRACT

Topical fungicidal composition for dermatomycosis of animals which comprises, as an active component, a 2-hydrazinotropone derivative having the formula   OR AN ACID ADDITION SALT THEREOF, WHEREIN R1 represents an alkyl group having from one to four carbon atoms or a phenyl group which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X represents hydrogen atom or an alkyl group having from one to four carbon atoms together with a suitable carrier. The composition may be preferably used in aerosol form.

United States Patent [191 Kitano et al.

[ Nov. 18, 1975 [22] Filed: Jan. 7, 1974 [21] Appl. No.: 431,030

[30] Foreign Application Priority Data Jan. 27, 1973 Japan 48-11506 [52] US. Cl. 424/45; 424/327 [51] Int. Cl. A6ll 9/04;'A6lk 31/15 [58] Field of Search 424/327, 45

[56] References Cited OTl-IER PUBLICATIONS Chemical Abstracts 63:4276h (1965).

Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmFlynn & Frishauf '57 ABSTRACT Topical fungicidal composition for dermatomycosis of animals which comprises, as an active component, a 2-hydrazinotropone derivative having the formula NH-NHR or an acid addition salt thereof, wherein R represents an alkyl group having from one to four carbon atoms or a phenyl group which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X represents hydrogen atom or an alkyl group having from one to four carbon atoms together with a suitable carrier. The composition may be preferably used in aerosol form.

8 Claims, No Drawings TOPICAL FUNGI CIDAL COMPOSITION FOR DERMATOMYCOSIS OF ANIMALS This invention relates to novel topical fungicidal ponent, a 2-hydrazinotropone derivative having the formula NH-NHR or an acid addition salt thereof, wherein R represents an alkyl group having from one to four carbon atoms or I I pound (I) with a mineral acid such as hydrochloric a phenyl group which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X represents hydrogen atom or an alkyl group having from one to four carbon atoms together with a suitable carrier.

Dermatomycosis of animals is generally called ringworm and is a skin disease caused by various dermatophytes. The disease occurs on skins of various'animals such as horse, cow, pig, cat, monkey, goat andchicken and appendages of skins such as hair, feather or claw. In the disease, there is recognized'clinical finding of circular alopecia and thickened crust. Treatment of the disease is important not only for health of animals but 2 also in thematters of public health, as the disease is infective to both human beings and animals.

Hitherto, physiotherapy, topical treatment and internal administration treatment have been applied to the treatment of dermatomycosis, but enough curing effects have not been obtained by topical treatment agents.

It was found that, as the results of extensive studies, the 2-hydrazinotropone derivatives having the above formula (I) and their acid addition salts were very useful for topical treatment of dermatomycosis of animals.

In the above formula (I), the'alkyl group of R and X is, for example, methyl, ethyl, propyl, isopropyl and butyl and the substituted phenyl group of R is, for example, phenyl group substituted at 0-, mor p-position with alkyl such as methyl, ethyl, propyl, isopropyl and butyl, halogen such as chlorine and bromine, nitro or alkoxy such as methoxy, ethoxy, propoxy, isopropoxy and butoxy. The salts of the compound (I) are dermatologically acceptable acid addition salts of the comacid, hydrobromic acid or sulfuric acid or with an organic acid such as p-toluenesulfonic acid, oxalic acid, citric acid or acetic acid.

The especially favorable compounds (I) according to this invention are those in which R is a phenyl group which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms. The most effective compound is that in which R, is unsubstituted phenyl group and X is hydrogen atom.

Minimum inhibitory concentrations (MIC) of the compounds having the formula (1) were shown in the Table 1.

Table l MIC of the Compounds (1) (meg/ml.)

Compounds" 1 2 3 4 5 6 7 8 9 10 1 1 12 13 Organisms SlaphyIucuccus 1.5 6.2 6.2 25 25 l 5 l 5 6 2 1.5 1 5 1 5 l 5 l 5 aui'enx 209 P Staph. 3.1 25 25 25 6 2 6.2 25 6.2 1 5 6. 6.2 6.2 aureus v (Resistant) Escherichia 100 100 100 100 25 100 100 100 100 100 100 100 100 coli NIH] Shigella 12.5 100 100 100 6.2 100 25 100 25 25 100 100 25 flexneri 2a Sh. 12.5 100 100 100 6.2 100 100 100 100 100 100 100 100 flexneri 16 (Resistant) Pseudomvnas 100 100 100 100 100 100 100 100 100 100 100 100 I00 aeruginosa Candida 6.2 6.2 25 100 100 100 100 25 100 100 1 ()0 100 25 albicans Trichaphywn 0.4 6.2 6 2 25 25 25 6.2 25 6.2 6.2 25 25 6.2 astzroides Tri. 0.8 100 6 2 25 25 25 25 25 6.2 6.2 25 25 25 imerdigimle Tri. 0.4 6.2 1.5 6.2 6.2 25 6.2 1 5 1.5 1.5 1 5 6.2 1 5 rubrum "r cultivated in Neutrient Agar at 37C. for 18 hours. cultivated in Sabourauds Agar at 27C. for 48 hours.

cultivated in Sabourauds Agar at 27C. for one week.

2-( 2 '-Phenylhydrazino )tropone 2-( 2 '-p-Chlorophenylh'ydrazino )tropone 2-( 2 '-m-Chlorophenylhydrazino )tropone 2-( 2 '-m-Nitropheny1hydrazino )tropone.

2-( 2 -p-Tolylhydrazino)tropone 2-( 2 '-o-Toly1hydrazino)tropone 2-( 2 '-m-Tolylhydrazino)tropone 2-( 2-o-Methoxyphenylhydrazino )tropone 2-( 2-p-Methoxyphenylhydrazino )tropone (10) (ll) (l2) Z-Hydrazinotropone derivatives (1) of this invention are easily prepared by the reaction of 2*methoxytropone derivatives (11) with hydrazine derivatives (III) according to a known method, for example, the method described in Chem. Pharm. Bull. 13 (4), 457-464 U965).

X n u-mm S X OCH (II) (III) In the above formulae, R and X are the same as above.

The compositions containing the compounds of the formula (I) used for a treatment of dermatomycosis of animals may be employed in a form of embrocation agents, ointments, medicated bath agents and, most preferebly, aerosoles and these preparations may be prepared by usual methods.

The compositions of this invention may include one or more of the following additives; a solvent such as ethanol. benzyl alcohol or glycol salicylate, keratolytics such as salicylic acid, chrysarobin, unsaturated fatty acid such as undecylenic acid and optionally further known fungicides such as pentachlorophenol. thiabendazole. haloprogin and griseofulvin.

The amount of the active component to be incorporated into the preparation is 0.01 5 7: (w/v), preferably 0.1 2 7: (w/v) and the preparation is usually applied to lesion parts of the infected animals for 3-14 days.

The compounds (I) of this invention show low toxicities to animals. For example, acute toxicities of 2-(2'- phenylhydrazino)tropone to mice were shown in the Table II.

administration Examples and clinical data of the composition of this invention are shown below.

EXAMPLE Aerosol 2-(2'-Phenylhydrazino)tropone Benzyl alcohol Ethanol (99%) Freon-l2 (Du Pont) dichlorodifluoromethane Freon-l l (Du Pont) trichlorofluoromethane The 2-(2'-phenylhydrazino)tropone was dissolved in the mixture of the benzyl alcohol and the ethanol at room temperature and the solution was put into an aerosol container. The propellents were filled into the container through the valve attached thereto.

The concentration of the active component was one percent by weight per volume.

1. The above aerosol was applied to the lesion of dermatomycosis of milch cows (age 6-8 months, female of Holstein) once a day for a week. The results are shown in the Table Ill.

Table III Clinical Data in Cows Clinical Condition I Effectiveness No. Position of lesions size (cm) Clinical findings after one week after 4 weeks I Left abdominal part 4.5 X 3.0 severe thick crust start to grow cured and strong fallinghair out of hair 4.0 X 3.5 thick crust and start to grow cured 2 Left neck part middle falling-out hair of hair 2.8 X 2 5 thick crust and starts to grow cured middle fallingout hair of hair 2.6 X 4.0 falling-out of grows hair on cured 3 Lower part of hair the central area Table III -cntinued Clinical Data in Cows Clinical Condition Effectiveness No. Position of lesions size cm') Clinical findings after oneweek after 4 weeks Left shoulder 1.8 X 2.2 falling-out of starts to grow cured hair hair 3.2 X 2.7 falling-out of starts to grow cured 4 Right neck part hair hair 4.0 X 3.5 falling-out of starts to grow cured hair hair 5.0 X 2.l falling-out of starts to grow cured 5 Lower part of hair hair vulva I 3.5 X 3.0 falling-out of starts to grow cured hair hair 2. The above aerosol was applied to the lesion of der- O matomycosis of 8 horses (age 3-5 years, male and female of Thoroughbred) once a day for 5 7 days. X (I) As the results, the hair started to grow after one week and the lesion was completely cured after 1 four weeks.

i wherein R represents alkyl having from one to four What is claimed is:

1. A topical fungicidal composition which comprises, as an active component in an amount sufficient to inhibit dermatomycosis of an animal, a 2-hydrazinotropone having the formula NH-NHR or a dermatologically acceptable acid addition salt 2. The topical fungicidal composition of claim 1 wherein said active component is a Z-hydrazinotropone having the formula (I) or a dermatologically acceptable acid addition salt thereof wherein R is phenyl which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X is hydrogen atom.

3. The topical fungicidal composition of claim 1 wherein the Z-hydrazinotropone is 2-(2'-phenylhydrazino)tropone.

4. An aerosol composition confined under pressure in an aerosol dispensing container comprising a 2- hydrazinotropone or a dermatologically acceptable acid addition salt thereof in an amount of from about 0.01 to about 5 percent by weight of said composition, a solvent selected from the group consisting of ethanol, benzyi alcohol and glycol salicylate and a propellant mixture of about percent by weight of trichlorofluoromethane and about 30 percent by weight of dichlorodifluoromethane, said Z-hydrazinotropone having the formula carbon atoms or phenyl which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms, X represents hydrogen or alkyl having from one to four carbon atoms.

' 5. A topical fungicidal composition which comprises, as an active component in an amount sufficient to inhibit dermatomycosis of an animal, a 2-hydrazinotro-' pone having the formula from one to four carbon atoms together with glycol sal- 'icylate.

6. A process for the treatment of dermatomycosis of an animal which comprises administering topically to saidanimal a composition comprising an amount sufficient to inhibit dermatomycosis of an animal of a 2- hydrazinotropone having the formula or a dermatologically acceptable acid addition salt thereof, wherein R represents alkyl having from one to four carbon atoms or phenyl which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having froiii on to four carbon atoms, X represents hyd rog'eii 6? alkyl having nan. one

7 8 to four carbon atoms together with a dermatologically halogen, alkyl having from one to four carbon atoms, acceptable carrier therefor. nitro or alkoxy having from one to four carbon atoms 7. A process of claim 6 wherein said active compoand X is hydrogen atom.

nent is a Z-hydrazinotropone having the formula (I) or 8; A process of claim 6 wherein the 2-hydrazinot'roa dermatologically acceptable acid addition salt thereof pone is 2-( 2-phenylhydrazino)tropone. wherein R is phenyl which may be substituted with UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,920,843 Dated November 18, 1975 Inventor-(S) Noritoshi Kitano et a].-

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns l-Z, Table l: at "Staphlococcus aureus 209P", under "6" H7", "9", "10" "ll", "12" 1'13" "Staph. aureus [Resistant)", under "10", insert i before "1.5".

Signed and Scaled this RUTH C. MASON Attesting Officer C. MARSHALL DANN Commissioner uj'larenls and Trademarks 

1. A TOPICAL FUNGICIDAL COMPOSITION WHICH COMPRISES, AS AN ACTIVE COMPONENT IN AN AMOUNT SUFFICIENT TO INHIBIT DERMATOMYCOSIS OF AN ANIMAL, A 2-HYDRAZINOTROPONE HAVING THE FORMULA
 2. The topical fungicidal composition of claim 1 wherein said active component is a 2-hydrazinotropone having the formula (I) or a dermatologically acceptable acid addition salt thereof wherein R1 is phenyl which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X is hydrogen atom.
 3. The topical fungicidal composition of claim 1 wherein the 2-hydrazinotropone is 2-(2''-phenylhydrazino)tropone.
 4. An aerosol composition confined under pressure in an aerosol dispensing container comprising a 2-hydrazinotropone or a dermatologically acceptable acid addition salt thereof in an amount of from about 0.01 to about 5 percent by weight of said composition, a solvent selected from the group consisting of ethanol, benzyl alcohol and glycol salicylate and a propellant mixture of about 30 percent by weight of trichlorofluoromethane and about 30 percent by weight of dichlorodifluoromethane, said 2-hydrazinotropone having the formula
 5. A topical fungicidal composition which comprises, as an active component in an amount sufficient to inhibit dermatomycosis of an animal, a 2-hydrazinotropone having the formula
 6. A process for the treatment of dermatomycosis of an animal which comprises administering topically to said animal a composition comprising an amount sufficient to inhibit dermatomycosis of an animal of a 2-hydrazinotropone having the formula
 7. A process of claim 6 wherein said active component is a 2-hydrazinotropone having the formula (I) or a dermatologically acceptable acid addition salt thereof wherein R1 is phenyl which may be substituted with halogen, alkyl having from one to four carbon atoms, nitro or alkoxy having from one to four carbon atoms and X is hydrogen atom.
 8. A process of claim 6 wherein the 2-hydrazinotropone is 2-(2''-phenylhydrazino)tropone. 